Atherosclerosis is a multifactorial disease characterized by excessive intracellular lipid deposition in macrophages, leading to formation of foam cells. The accumulation of lipid-loaded foam cells in the subendothelial space leads to formation of fatty streaks, which are the early atherosclerotic lesions.
Oxidative modification of lipids, specifically low-density lipoprotein, has been implicated as a major process in foam-cell formation.
Lipoxygenases are nonheme iron-containing enzymes that catalyze the oxygenation of certain polyunsaturated fatty acids such as lipoproteins. Several different lipoxygenase enzymes are known, each having a characteristic oxidation action. One specific lipoxygenase, namely 15-LO, has been detected in atherosclerotic lesions in mammals, specifically rabbit and man. The enzyme, in addition to its role in oxidative modification of lipoproteins, is important in the inflammatory reaction in the atherosclerotic lesion. Indeed, 15-LO has been shown to be induced in human monocytes by the cytokin IL-4, which is known to be implicated in the inflammatory process.
Another class of lipoxygenase enzymes is 5-lipoxygenase (5-LO). While this enzyme causes oxidation of unsaturated fatty acids, it primarily is responsible for inserting oxygen on position 5 of arachidonic acid. Other lipoxygenases are known; one of the most common and abundant being 12-lipoxygenase (12-LO).
We have now found that inhibitors of 15-LO are especially useful to prevent and treat inflammation and atherosclerosis. While there are several lipoxygenase enzymes, specific inhibition of 15-LO is critical in the inflammatory and atherosclerosis process. All that is required according to this invention is to administer a 15-LO inhibitor, and especially one that is a specific 15-LO inhibitor.
Several classes of organic compounds are 15-LO inhibitors.
Tetracyclic indole and benzopyranoindole compounds are potent 15-LO inhibitors. U.S. Pat. No. No. 3,388,133 describes benz[b]indolo[2,3-d]-thiopyrano and pyrylium salts as antibacterial and antifungal agents. U.S. Pat. No. 4,132,714 describes a process for making chromenoindoles, which are said to be useful as color-forming agents. U.S. Pat. No. 4,797,495 discloses a wide variety of benzocarbazoles which are said to be antitumor agents. Similarly, benzimidazoles are well known as antiviral agents. U.S. Pat. No. 4,293,558 describes various 1-thiazolinyl-2-aminobenzimidazoles, and U.S. Pat. No. 4,243,813 describes 1-sulfonyl-benzimidazoles. None of those compounds have been described as inhibitors of 15-LO, and none have been utilized in treating inflammation or atherosclerosis. All of these compounds are 15-LO inhibitors and can be employed in the method of this invention.
We have now discovered that compounds which are effective inhibitors of 15-LO are useful in treating and preventing inflammation and atherosclerosis.